Arylvinylazacycloalkane compounds and methods of preparation and use thereof

ABSTRACT

Novel vinylazacycloalkane compounds of Formula (I) are disclosed. The compounds are ligands of various nAChRs. The compounds and their pharmaceutically acceptable salts can be used to prepare pharmaceutical compositions and/or medicaments intended to prevent or treat disorders associated with dysfunction of nAChRs, especially within the central nervous system or the gastrointestinal system. Examples of types of disorders that can be treated include neurodegenerative disorders, including central nervous system disorders such as Alzheimer&#39;s disease, cognitive disorders, motor disorders such as Parkinson&#39;s disease, drug addiction, behavioral disorders and inflammatory disorders within the gastrointestinal system. The compounds can also serve as analgesics in the treatment of acute, chronic or recurrent pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No.11/206,243 filed Aug. 17, 2005 now abandoned, which is a divisional ofU.S. application Ser. No. 10/379,868, filed Mar. 5, 2003, now U.S. Pat.No. 7,098,331 and is copending with U.S. application Ser. No.12/187,584, filed Aug. 7, 2008, each of which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositionsincorporating compounds capable of affecting nicotinic acetylcholinergicreceptors (nAChRs), for example, as modulators of specific nicotinicreceptor subtypes. The present invention also relates to methods fortreating a wide variety of conditions and disorders, particularly thoseassociated with dysfunction of the central and autonomic nervoussystems.

BACKGROUND OF THE INVENTION

Nicotine has been proposed to have a number of pharmacological effects.See, for example, Pullan et al., N. Engl. J. Med. 330:811-815 (1994).Certain of those effects can be related to effects upon neurotransmitterrelease. Release of acetylcholine, dopamine, norepinephrine, serotoninand glutamate upon administration of nicotine has been reported (Rowellet al., J. Neurochem. 43:1593 (1984); Rapier et al., J. Neurochem.50:1123 (1988); Sandor et al., Brain Res. 567:313 (1991) and Vizi, Br.J. Pharmacol. 47:765 (1973); Hall et al., Biochem. Pharmacol. 21:1829(1972); Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977); andToth et al., Neurochem Res. 17:265 (1992)). Confirmatory reports andadditional recent studies have included the modulation in the CentralNervous System (CNS) of glutamate, nitric oxide, GABA, takykinins,cytokines and peptides (reviewed in Brioni et al., Adv. Pharmacol.37:153 (1997)). In addition, nicotine reportedly potentiates thepharmacological behavior of certain pharmaceutical compositions used totreat certain disorders. See, for example, Sanberg et al., Pharmacol.Biochem. & Behavior 46:303 (1993); Harsing et al., J. Neurochem. 59:48(1993) and Hughes, Proceedings from Intl. Symp. Nic. S40 (1994).Furthermore, the neuroprotective effects of nicotine have been proposed,see, for example, Sjak-shie et al., Brain Res. 624:295 (1993). Variousother beneficial pharmacological effects have also been proposed. See,for example, Decina et al., Biol. Psychiatry 28:502 (1990); Wagner etal., Pharmacopsychiatry 21:301 (1988); Pomerleau et al., AddictiveBehaviors 9:265 (1984); Onaivi et al., Life Sci. 54(3):193 (1994);Tripathi et al., J. Pharmacol. Exp. Ther. 221:91 (1982) and Hamon,Trends in Pharmacol. Res. 15:36 (1994).

Various compounds that target nAChRs have been reported as being usefulfor treating a wide variety of conditions and disorders. See, forexample, Williams et al., DN&P 7(4):205 (1994); Arneric et al., CNS DrugRev. 1(1):1 (1995); Arneric et al., Exp. Opin. Invest. Drugs 5(1):79(1996); Bencherif et al., J. Pharmacol. Exp. Ther. 279:1413 (1996);Lippiello et al., J. Pharmacol. Exp. Ther. 279:1422 (1996); Damaj etal., J. Pharmacol. Exp. Ther. 291:390 (1999); Chiari et al.,Anesthesiology 91:1447 (1999); Lavand'homme and Eisenbach,Anesthesiology 91:1455 (1999); Holladay et al., J. Med. Chem. 40(28):4169 (1997); Bannon et al., Science 279: 77 (1998); PCT WO 94/08992, PCTWO 96/31475, PCT WO 96/40682, and U.S. Pat. No. 5,583,140 to Bencherifet al., U.S. Pat. No. 5,597,919 to Dull et al., U.S. Pat. No. 5,604,231to Smith et al. and U.S. Pat. No. 5,852,041 to Cosford et al. Nicotiniccompounds are reported as being particularly useful for treating a widevariety of CNS disorders. Indeed, a wide variety of nicotinic compoundshave been reported to have therapeutic properties. See, for example,Bencherif and Schmitt, Current Drug Targets: CNS and NeurologicalDisorders 1(4): 349-357 (2002), Levin and Rezvani, Current Drug Targets:CNS and Neurological Disorders 1(4): 423-431 (2002), O'Neill, et al.,Current Drug Targets: CNS and Neurological Disorders 1(4): 399-411(2002), U.S. Pat. No. 5,1871,166 to Kikuchi et al., U.S. Pat. No.5,672,601 to Cignarella, PCT WO 99/21834 and PCT WO 97/40049, UK PatentApplication GB 2295387 and European Patent Application 297,858.

CNS disorders are a type of neurological disorder. CNS disorders can bedrug induced; can be attributed to genetic predisposition, infection ortrauma; or can be of unknown etiology. CNS disorders compriseneuropsychiatric disorders, neurological diseases and mental illnesses,and include neurodegenerative diseases, behavioral disorders, cognitivedisorders and cognitive affective disorders. There are several CNSdisorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto a deficiency of acetylcholine, dopamine, norepinephrine and/orserotonin. Relatively common CNS disorders include pre-senile dementia(early-onset Alzheimer's disease), senile dementia (dementia of theAlzheimer's type), micro-infarct dementia, AIDS-related dementia,vascular dementia, Creutzfeld-Jakob disease, Pick's disease,Parkinsonism including Parkinson's disease, Lewy body dementia,progressive supranuclear palsy, Huntington's chorea, tardive dyskinesia,hyperkinesia, epilepsy, mania, attention deficit disorder, anxiety,dyslexia, schizophrenia, depression, obsessive-compulsive disorders andTourette's syndrome.

There exist subtypes of nAChRs in both the central and peripheralnervous systems, but the distribution of subtypes is heterogeneous. Forinstance, the subtypes which are predominant in vertebrate brain areα4β2, α7, and α3β2, whereas those which predominate at the autonomicganglia are α3β4 and those of neuromuscular junction are α1β1δγ andα1β1δε (see for instance Dwoskin et al., Exp. Opin. Ther. Patents 10:1561 (2000) and Schmitt and Bencherif, Annual Reports in Med. Chem. 35:41 (2000)). A limitation of some nicotinic compounds is that they elicitvarious undesirable pharmacological effects because of their interactionwith nAChRs in peripheral tissues (for example, by stimulating muscleand ganglionic nAChR subtypes). It would be desirable to have compounds,compositions and methods for preventing and/or treating variousconditions or disorders (e.g., CNS disorders), including alleviating thesymptoms of these disorders, where the compounds exhibit nicotinicpharmacology with a beneficial effect on the CNS nAChRs (e.g., upon thefunctioning of the CNS), but without significant associated effects onthe peripheral nAChRs (compounds specific for CNS nAChRs). It wouldfurther be highly desirable to provide compounds, compositions andmethods that affect CNS function without significantly affecting thosereceptor subtypes which have the potential to induce undesirable sideeffects (e.g., appreciable activity at cardiovascular and skeletalmuscle sites). The present invention provides such compounds,compositions and methods.

SUMMARY OF THE INVENTION

The present invention relates to the vinylazacycloalkane compounds ofFormula (I):

wherein:

the wavy line represents variable geometry (E or Z) about the doublebond;

X is nitrogen or C—R²;

R¹ is hydrogen, C₁₋₆-alkyl, halogen, —OR⁴, —NR⁴R⁵, or —SR⁴ when X isC—R² and hydrogen, C₁₋₆ alkyl, —OR⁴, or —NR⁴R⁵ when X is nitrogen;

R² is hydrogen, C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, C₁₋₆-alkyl-aryl,heteroaryl, heteroaryl-C₁₋₆-alkyl, heterocyclyl, heterocycloalkyl,cycloalkyl, polycycloalkyl, —OR⁶, —NR⁶R⁷, —SR⁶, —SOR⁶, or —SO₂R⁶, eachof which can optionally be substituted with 1 or more substituentsselected from halogen, —CN, —NO₂, —NH₂, —OH, —OR⁶, —COOH, —C(O)OR⁶,—O—C(O)R⁶, —NR⁶R⁷, —NHC(O)R⁶, —C(O)NR⁶R⁷, —SR⁶, —S(O)R⁶, —SO₂R⁶,—NHSO₂R⁶, —SO₂NR⁶R⁶, —C(S)NR⁶R⁶, —NHC(S)R⁶, —O—SO₂R⁶, aryl, heteroaryl,formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, andC₁₋₆ alkyl;

R³ is hydrogen, C₁₋₆-alkyl, aryl-C₁₋₆-alkyl, heteroaryl C₁₋₆-alkyl,heterocyclyl, heterocycloalkyl, cycloalkyl or polycycloalkyl;

m is between 1 and 4;

n is between 1 and 3;

R⁴ and R⁵ are, independently, hydrogen or C₁₋₆-alkyl;

R⁶ and R⁷ are, independently, hydrogen, C₁₋₆-alkyl, aryl,aryl-C₁₋₆-alkyl, heteroaryl, heteroaryl-C₁₋₆-alkyl, heterocyclyl,heterocyclylalkyl, cycloalkyl or polycycloalkyl, each of which canoptionally be substituted with one or more substituents selected fromthe group consisting of halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —CN, —NO₂,—NH₂, —OH, —COOH, —COO—C₁₋₆ alkyl, —CONH₂, formyl, trifluoromethyl andtrifluoromethoxy,

wherein the C₁₋₆-alkyl, heterocyclyl, heteroaryl and aryl groups can besubstituted with from 1-6 substituents selected from the groupconsisting of F, Cl, Br, I, R⁸, —NR⁸R⁹, —CF₃, —CN, —NO₂, —C₂R⁸, —N₃,—SO₂CH₃, —OR⁸, —SR⁸, —C(═O)NR⁸R⁹, —NR⁸C(═O)R⁸, —C(═O)R⁸, —C(═O)OR⁸,—(CH₂)_(q)OR⁸, —OC(═O)R⁸, —OC(═O)NR⁸R⁹ and —NR⁸C(═O)OR⁸,

where R⁸ and R⁹ are individually hydrogen or lower alkyl (e.g., C₁-C₆alkyl, preferably methyl, ethyl, isopropyl or isobutyl), an aromaticgroup-containing species or a substituted aromatic group-containingspecies (substituted with one or more of the above substituents).

Either R⁶ and R⁷ or R⁸ and R⁹ can also form a C₁₋₁₀ cycloalkylfunctionality (e.g., cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and adamantyl). Representative aromatic group-containingspecies include pyridyl, quinolinyl, pyrimidinyl, phenyl, and benzyl(where any of the foregoing can be suitably substituted with at leastone substituent group as defined above, specifically including loweralkyl, halo, and/or amino substituents). Other representative aromaticring systems are set forth in Gibson et al., J. Med. Chem. 39:4065(1996).

Isomers, mixtures, including racemic mixtures, enantiomers,diastereomers and tautomers of these compounds as well aspharmaceutically acceptable salts thereof, are also included.

The present invention relates more particularly to derivatives ofFormula (I) in which:

the geometry at the double bond is E;

X is N or C—R²;

R¹ is hydrogen;

R² is —OR⁶;

R³ is hydrogen;

n is 1;

m is 2; and

R⁶ is a alkyl, aryl or heterocyclyl; and

isomers thereof, mixtures thereof, including racemic mixtures,enantiomers, diastereomers and tautomers thereof, and pharmaceuticallyacceptable salts thereof, and to their use as ligands of nAChRs.

The compounds of Formula (I) and their pharmaceutically acceptable saltscan be used to prepare pharmaceutical compositions and/or medicamentsintended to prevent the disorders or to treat the diseases associatedwith dysfunction of the nAChRs, especially within the central nervoussystem or the gastrointestinal system. The term “to treat” can coverboth beneficial effects on the symptoms and/or on the course of thecondition under consideration.

Examples of types of disorders that can be treated includeneurodegenerative disorders, including central nervous system disorderssuch as Alzheimer's disease and other dementia, motor disorders such asParkinson's disease, drug addiction, behavioral disorders andinflammatory disorders within the gastrointestinal system. The compoundscan also serve as analgesics, for example, in the treatment of acute,chronic or recurrent pain.

DETAILED DESCRIPTION OF THE INVENTION

The compounds, compositions and methods described herein will be betterunderstood with reference to the following preferred embodiments. Thefollowing definitions will be useful in defining the scope of theinvention:

As used herein, “aromatic” refers to 3 to 10, preferably 5 and6-membered ring aromatic and heteroaromatic rings.

As used herein, “aromatic group-containing species” refer to moietiesthat are or include an aromatic group. Accordingly, phenyl and benzylmoieties are included in this definition, as both are or include anaromatic group.

As used herein, C₁₋₆ alkyl radicals (lower alkyl radicals) contain from1 to 6 carbon atoms in a straight or branched chain, and also includeC₃₋₆ cycloalkyl moieties and alkyl radicals that contain C₃₋₆ cycloalkylmoieties.

As used herein, C₁₋₆ alkoxy radicals contain from 1 to 6 carbon atoms ina straight or branched chain, and also include C₃₋₆ cycloalkyl andalkoxy radicals that contain C₃₋₆ cycloalkyl moieties.

As used herein, aryl radicals are selected from phenyl, naphthyl andindenyl.

As used herein, heteroaryl radicals contain from 3 to 10 members,preferably 5 or 6 members, including one or more heteroatoms selectedfrom oxygen, sulfur and nitrogen. Examples of suitable 5 membered ringheteroaryl moieties include furyl, thiophenyl, pyrrolyl, imidazolyl,oxazolyl, thiazolyl, thienyl, tetrazolyl, and pyrazolyl. Examples ofsuitable 6 membered ring heteroaryl moieties include pyridinyl,pyrimidinyl, pyrazinyl, of which pyridinyl and pyrimidinyl arepreferred.

As used herein, halogen is chlorine, iodine, fluorine or bromine.

As used herein, polycycloalkyl radicals are fused cyclic ringstructures.

Representative polycycloalkyl radicals include, but are not limited to,adamantyl, bornanyl, norbornanyl, bornenyl and norbornenyl.Polycycloalkyl radicals can also include one or more heteroatoms, suchas N, O or S.

As used herein, heterocyclyl radicals contain from 3 to 10 membersincluding one or more heteroatoms selected from oxygen, sulfur andnitrogen. Examples of suitable heterocyclyl moieties include, but arenot limited to, piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, isothiazolidinyl, thiazolidinyl, isoxazolidinyl,oxazolidinyl, piperazinyl, tetrahydropyranyl and tetrahydrofuranyl.

As used herein, cycloalkyl radicals contain from 3 to 8 carbon atoms.Examples of suitable cycloalkyl radicals include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

Examples of suitable pharmaceutically acceptable salts include inorganicacid addition salts such as chloride, bromide, sulfate, phosphate, andnitrate; organic acid addition salts such as acetate, galactarate,propionate, succinate, lactate, glycolate, malate, tartrate, citrate,maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate;salts with acidic amino acid such as aspartate and glutamate; alkalimetal salts such as sodium salt and potassium salt; alkaline earth metalsalts such as magnesium salt and calcium salt; ammonium salt; organicbasic salts such as trimethylamine salt, triethylamine salt, pyridinesalt, picoline salt, dicyclohexylamine salt, andN,N′-dibenzylethylenediamine salt; and salts with basic amino acid suchas lysine salt and arginine salt. The salts may be in some caseshydrates or ethanol solvates. Representative salts are provided asdescribed in U.S. Pat. Nos. 5,597,919 to Dull et al., 5,616,716 to Dullet al. and 5,663,356 to Ruecroft et al.

As used herein, an “agonist” is a substance that stimulates its bindingpartner, typically a receptor. Stimulation is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Stimulation may be defined with respect to anincrease in a particular effect or function that is induced byinteraction of the agonist or partial agonist with a binding partner andcan include allosteric effects.

As used herein, an “antagonist” is a substance that inhibits its bindingpartner, typically a receptor. Inhibition is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Inhibition may be defined with respect to adecrease in a particular effect or function that is induced byinteraction of the antagonist with a binding partner, and can includeallosteric effects.

As used herein, a “partial agonist” is a substance that provides a levelof stimulation to its binding partner that is intermediate between thatof a full or complete antagonist and an agonist defined by any acceptedstandard for agonist activity. It will be recognized that stimulation,and hence, inhibition is defined intrinsically for any substance orcategory of substances to be defined as agonists, antagonists, orpartial agonists. As used herein, “intrinsic activity”, or “efficacy,”relates to some measure of biological effectiveness of the bindingpartner complex. With regard to receptor pharmacology, the context inwhich intrinsic activity or efficacy should be defined will depend onthe context of the binding partner (e.g., receptor/ligand) complex andthe consideration of an activity relevant to a particular biologicaloutcome. For example, in some circumstances, intrinsic activity may varydepending on the particular second messenger system involved. See Hoyer,D. and Boddeke, H., Trends Pharmacol Sci. 14(7):270-5 (1993). Where suchcontextually specific evaluations are relevant, and how they might berelevant in the context of the present invention, will be apparent toone of ordinary skill in the art.

As used herein, neurotransmitters whose release is mediated by thecompounds described herein include, but are not limited to,acetylcholine, dopamine, norepinephrine, serotonin and glutamate, andthe compounds described herein function as agonists or partial agonistsat one or more of the CNS nAChRs.

I. Compounds

The compounds of Formula (I) have one or more asymmetric carbons and cantherefore exist in the form of isomers, racemic mixtures, enantiomersand diastereomers. These individual compounds and their mixtures areintended to be within the scope of the present invention.

The following are representative compounds of Formula (I):

-   (R)- and    (S)-3-((E)-2-pyrrolidin-3-ylvinyl)-5-(tetrahydropyran-4-yloxy)pyridine-   (R)- and (S)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine-   (R)- and (S)-2-chloro-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine-   (R)- and (S)-3-isopropoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine-   (R)- and    (S)-3-isopropoxy-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyridine-   (R)- and    (S)-3-cyclopropylmethoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine-   (R)- and (S)-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyrimidine-   (R)- and    (S)-2-chloro-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyridine-   (R)- and    (S)-3-cyclopropylmethoxy-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyridine-   (R)- and (S)-5-((E)-2-piperidin-3-ylvinyl)pyrimidine-   (R)- and (S)-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyrimidine-   (R)- and (S)-2-chloro-5-((E)-2-piperidin-3-ylvinyl)pyridine-   (R)- and    (S)-2-chloro-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyridine-   (R)- and    (S)-3-cyclopropylmethoxy-5-((E)-2-piperidin-3-ylvinyl)pyridine-   (R)- and    (S)-3-cyclopropylmethoxy-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyridine-   5-((E)-2-piperidin-4-ylvinyl)pyrimidine-   5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyrimidine-   2-chloro-5-((E)-2-piperidin-4-ylvinyl)pyridine-   2-chloro-5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyridine-   3-cyclopropylmethoxy-5-((E)-2-piperidin-4-ylvinyl)pyridine-   3-cyclopropylmethoxy-5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyridine-   5-((E)-2-azetidin-3-ylvinyl)pyrimidine-   5-((E)-2-(1-methylazetidin-3-yl)vinyl)pyrimidine-   5-((E)-2-azetidin-3-ylvinyl)-2-chloropyridine-   5-((E)-2-(1-methylazetidin-3-yl)vinyl)-2-chloropyridine-   3-((E)-2-azetidin-3-ylvinyl)-5-cyclopropylmethoxypyridine-   3-((E)-2-(1-methylazetidin-3-yl)vinyl)-5-cyclopropylmethoxypyridine-   (R)- and (S)-3-phenoxy-5-((E)-2-piperidin-3-ylvinyl)pyridine-   (R)- and    (S)-3-phenoxy-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyridine-   3-phenoxy-5-((E)-2-piperidin-4-ylvinyl)pyridine-   3-phenoxy-5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyridine-   3-phenoxy-5-((E)-2-azetidin-3-ylvinyl)pyridine and-   3-phenoxy-5-((E)-2-(1-methylazetidin-3-yl)vinyl)pyridine.

In each of these compounds, individual isomers thereof, mixturesthereof, including racemic mixtures, enantiomers, diastereomers andtautomers thereof, and the pharmaceutically acceptable salts thereof,are intended to be within the scope of the present invention.

II. Compound Preparation

While other synthetic strategies will be apparent to those of skill inthe art, the compounds of Formula (I) wherein R³ represents a hydrogencan be obtained from a compound of general formula (II) in accordancewith the following general synthesis scheme:

The general synthesis scheme is as follows:

a) an aldehyde of general formula (II) is reacted with the phosphoraneylide (III);

b) the vinylazacycloalkane of general formula (IV) is reacted with aheteroaryl halide of general formula (V, where Y=halogen);

c) the tert-butoxycarbonyl group is eliminated from the compound ofgeneral formula (VI);

and the product is isolated and optionally converted into apharmaceutically acceptable salt.

The reaction (a) between an aldehyde of general formula (II) and thephosphorane ylide (III) advantageously takes place under an inertatmosphere (for example under nitrogen or argon) in an inert solventsuch as tetrahydrofuran at a temperature between −10° C. and the boilingtemperature of the reaction mixture, preferably at a temperature betweenaround −5° C. and around 22° C.

The reaction (b) between a vinylazacycloalkane of general formula (IV)and an appropriate heteroaryl halide of general formula (V)advantageously takes place under an inert atmosphere in the presence ofa catalyst such as palladium acetate, a base such asdiisopropylethylamine and an inorganic salt such as lithium chloride, inan inert solvent such as dimethylformamide at a temperature between 20°C. and the boiling temperature of the reaction mixture. Ideally, thetemperature of the reaction is in the region of about 110° C.

In another embodiment, the reaction (b) between a vinylazacycloalkane ofgeneral formula (IV) and an appropriate heteroaryl halide of generalformula (V) can be performed preferably under an inert atmosphere (forexample under nitrogen or under argon) in the presence of a catalystsuch as palladium acetate and a phosphine such as triphenylphosphine inbasic medium, for example in the presence of a base such astriethylamine, at a temperature between 20° C. and the boilingtemperature of the reaction mixture, preferably at a temperature in theregion of 110° C.

The reaction (c) takes place generally in accordance with the customarymethods which do not adversely affect the rest of the molecule, inparticular by applications of the methods described by T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Synthesis (2nd ed.), A.Wiley—Interscience Publication (1991). For example, the reaction (c) ofeliminating the tert-butoxycarbonyl group from the compound of generalformula (VI) takes place preferably under an inert atmosphere (forexample under nitrogen or under argon) in the presence of an acid suchas trifluoroacetic acid in an inert solvent such as dichloromethane at atemperature between −10° C. and the boiling temperature of the reactionmixture, preferably at a temperature between −5° C. and a temperature inthe region of 22° C.

Alternatively the reaction (c) of eliminating the tert-butoxycarbonylgroup from the compound of general formula (VI) can be performedpreferably under an inert atmosphere (for example under nitrogen orunder argon) by the action of trimethylsilyl iodide in an inert solventsuch as dichloromethane at a temperature between −10° C. and the boilingtemperature of the reaction mixture, preferably at a temperature in theregion of 22° C.

The derivatives of general formula (I) in which R³ does not represent ahydrogen can be obtained from a compound of general formula (I) in whichR³ represents a hydrogen atom in accordance with the customary methodsof amine alkylation which do not adversely affect the rest of themolecule, in particular by applications of the methods described by R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989).

Alternatively the derivatives of general formula (I) in which R³represents a methyl can be obtained by reacting a compound of generalformula (I) in which R³ represents a hydrogen with a solution offormaldehyde in formic acid at a temperature between 22° C. and theboiling temperature of the reaction mixture.

The compounds of general formula (II) which are not commerciallyavailable can be obtained by applying or adapting methods described byPeschke B. et al., Eur. J. Med. Chem. 34:363-380 (1999), the contents ofwhich are hereby incorporated by reference.

The compounds of general formula (V) which are not commerciallyavailable can be obtained by applying or adapting methods described inPCT WO 00/75110, the contents of which are hereby incorporated byreference. Alternatively the compounds of general formula (V) in which

X is C—R²;

R² is —OR⁶; and

R⁶ is C₁₋₆ alkyl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl, heterocyclyl,heterocyclylalkyl, cycloalkyl or polycycloalkyls, these radicals beingoptionally substituted by 1 or more substituents selected from halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, —CN, —NO₂, —NH₂, —OH, —COOH, —COO—C₁₋₆ alkyl,—CONH₂, formyl, trifluoromethyl or trifluoromethoxy, can be obtainedfrom a heteroaryl halide of general formula (VII), where Y is a halogenand R¹ is as previously defined, and an alcohol of general formula(VIII), where R⁶ is as previously defined, in accordance with thefollowing general synthesis scheme:

The reaction (d) between heteroaryl alcohol of general formula (VII) andan appropriate alcohol of general formula (VIII) takes place preferablyunder an inert atmosphere in the presence of a diazene such as diethylazodicarboxylate and a phosphine such as triphenylphosphine in an inertsolvent such as toluene at a temperature between 0° C. and the boilingtemperature of the reaction mixture, preferably at a temperature betweena temperature in the region of 22° C. and the boiling temperature of thesolvent.

The compounds of general Formula (I) can be isolated and purified usingmethods well known to those of skill in the art, including, for example,crystallization, chromatography and/or extraction.

In the above-mentioned schemes, when any one or more of the R-groups areor contain reactive groups that are potentially reactive under thereaction conditions, for example, —OH, —SH, —NH₂ or —CO₂H, it will bereadily apparent to those of skill in the art that these functionalgroups can require the use of suitable “protecting groups” during thereactions to “block” the reactivity of the R-group. These “protecting”groups can be chosen, introduced and cleaved in accordance to T. W.Greene and P. G. M. Wuts (Protective Groups in Organic Synthesis (2nded.), A. Wiley—Interscience Publication (1991)).

The compounds of general formula (I) and the compounds of generalformula (IV) can be obtained in optically pure form by separating theirracemates in accordance with the customary methods (i.e., resolution ofenantiomers), or by using optically pure starting materials.

The compounds of general formula (I) can optionally be converted intoaddition salts with a mineral or organic acid by the action of such anacid in an appropriate solvent, for example, an organic solvent such asan alcohol, a ketone, an ether or a chlorinated solvent. These saltslikewise form part of the invention.

Representative pharmaceutically acceptable salts include, but are notlimited to, benzenesulfonate, bromide, chloride, citrate,ethanesulfonate, fumarate, gluconate, iodate, maleate, isethionate,methanesulfonate, methylenebis(β-oxynaphthoate), nitrate, oxalate,palmoate, phosphate, salicylate, succinate, sulfate, tartrate,theophyllinacetate, p-toluenesulfonate, hemigalactarate and galactaratesalts.

III. Pharmaceutical Compositions

The pharmaceutical compositions according to the invention include acompound of Formula (I) or a salt thereof, in the pure state or in theform of a composition in which it is combined with any otherpharmaceutically compatible product, which can be inert orphysiologically active. Such compositions can be administered, forexample, orally, parenterally, rectally or topically.

Examples of solid compositions for oral administration include, but arenot limited to, tablets, pills, powders (gelatin capsules, cachets) andgranules. In these compositions, the active compound is mixed with oneor more inert diluents, such as starch, cellulose, sucrose, lactose orsilica, ideally under a stream of an inert gas such as argon.

The compositions can also include substances other than diluents, forexample, one or more lubricants such as magnesium stearate or talc, acolorant, a coating (coated tablets) or a varnish.

Examples of liquid compositions for oral administration include, but arenot limited to, solutions, suspensions, emulsions, syrups and elixirsthat are pharmaceutically acceptable and typically contain inertdiluents such as water, ethanol, glycerol, vegetable oils or liquidparaffin. These compositions can comprise substances other than thediluents, for example, wetting agents, sweeteners, thickeners, flavorsand stabilizers.

Sterile compositions for parenteral administration can include, forexample, aqueous or nonaqueous solutions, suspensions and emulsions.Examples of suitable solvents and vehicles include, but are not limitedto aqueous solutions, preferably buffered aqueous solutions, propyleneglycol, a polyethylene glycol, vegetable oils, especially olive oil,injectable organic esters, for example ethyl oleate, and otherappropriate organic solvents. These compositions can also includeadjuvants, especially wetting agents, isotonicity agents, emulsifiers,dispersants and stabilizers. Such sterile compositions can be sterilizedin a number of ways, for example, by asepticizing filtration, byincorporating sterilizing agents into the composition, by irradiationand by heating. They can also be prepared in the form of sterile solidcompositions which can be dissolved at the time of use in sterile wateror any other sterile injectable medium.

Examples of compositions for rectal administration include, but are notlimited to, suppositories and rectal capsules that, in addition to theactive product, can include excipients such as cocoa butter,semi-synthetic glycerides and polyethylene glycols.

Compositions for topical administration can, for example, be creams,lotions, eyewashes, collutoria, nasal drops or aerosols.

The pharmaceutical compositions also can include various othercomponents as additives or adjuncts. Exemplary pharmaceuticallyacceptable components or adjuncts which are employed in relevantcircumstances include antioxidants, free radical scavenging agents,peptides, growth factors, antibiotics, bacteriostatic agents,immunosuppressives, anticoagulants, buffering agents, anti-inflammatoryagents, anti-pyretics, time release binders, anesthetics, steroids andcorticosteroids. Such components can provide additional therapeuticbenefit, act to affect the therapeutic action of the pharmaceuticalcomposition, or act towards preventing any potential side effects whichmay be posed as a result of administration of the pharmaceuticalcomposition. In certain circumstances, a compound of the presentinvention can be employed as part of a pharmaceutical composition withother compounds intended to prevent or treat a particular disorder.

IV. Methods of Treatment

The compounds described herein are useful for treating those types ofconditions and disorders for which other types of nicotinic compoundshave been proposed as therapeutics. See, for example, Williams et al.,DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1):1-26(1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79-100 (1996),Bencherif et al., J. Pharmacol. Exp. Ther. 279:1413 (1996), Lippiello etal., J. Pharmacol. Exp. Ther. 279:1422 (1996), Damaj et al.,Neuroscience (1997), Holladay et al., J. Med. Chem. 40(28): 4169-4194(1997), Bannon et al., Science 279: 77-80 (1998), PCT WO 94/08992, PCTWO 96/31475, and U.S. Pat. Nos. 5,583,140 to Bencherif et al., 5,597,919to Dull et al., and 5,604,231 to Smith et al.

The compounds can also be used as adjunct therapy in combination withexisting therapies in the management of the aforementioned types ofdiseases and disorders. In such situations, it is preferably toadminister the active ingredients in a manner that minimizes effectsupon nAChR subtypes such as those that are associated with muscle andganglia. This can be accomplished by targeted drug delivery and/or byadjusting the dosage such that a desired effect is obtained withoutmeeting the threshold dosage required to achieve significant sideeffects. The pharmaceutical compositions can be used to ameliorate anyof the symptoms associated with those conditions, diseases anddisorders.

Examples of conditions and disorders that can be treated includeneurological disorders, neurodegenerative disorders, in particular, CNSdisorders, and inflammatory disorders. CNS disorders can be druginduced; can be attributed to genetic predisposition, infection ortrauma; or can be of unknown etiology. CNS disorders compriseneuropsychiatric disorders, neurological diseases and mental illnesses,and include neurodegenerative diseases, behavioral disorders, cognitivedisorders and cognitive affective disorders. There are several CNSdisorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto a deficiency of choline, dopamine, norepinephrine and/or serotonin.

Examples of CNS disorders that can be treated using the compounds ofFormula (I) and their pharmaceutically acceptable salts, andpharmaceutical compositions including these compounds, includepre-senile dementia (early onset Alzheimer's disease), senile dementia(dementia of the Alzheimer's type), Lewy Body dementia, micro-infarctdementia, AIDS-related dementia, HIV-dementia, multiple cerebralinfarcts, Parkinsonism including Parkinson's disease, Pick's disease,progressive supranuclear palsy, Huntington's chorea, tardive dyskinesia,hyperkinesia, epilepsy, mania, attention deficit disorder, anxiety,depression, dyslexia, schizophrenia depression, obsessive-compulsivedisorders, Tourette's syndrome, mild cognitive impairment (MCI),age-associated memory impairment (AAMI), premature amnesic and cognitivedisorders which are age-related or a consequence of alcoholism, orimmunodeficiency syndrome, or are associated with vascular disorders,with genetic alterations (such as, for example, trisomy 21) or withattention deficiencies or learning deficiencies, acute or chronicneurodegenerative conditions such as amyotrophic lateral sclerosis,multiple sclerosis, peripheral neurotrophies, and cerebral or spinaltraumas. In addition, the compounds can be used to treat nicotineaddiction and/or other behavioral disorders related to substances thatlead to dependency (e.g., alcohol, cocaine, heroin and opiates,psychostimulants, benzodiazepines and barbiturates). The compounds canalso be used to treat pathologies exhibiting an inflammatory characterwithin the gastrointestinal system such as Crohn's disease, irritablebowel syndrome and ulcerous colitis, and in diarrheas.

The manner in which the compounds are administered can vary. Thecompounds can be administered by inhalation (e.g., in the form of anaerosol either nasally or using delivery articles of the type set forthin U.S. Pat. No. 4,922,901 to Brooks et al.); topically (e.g., in lotionform); orally (e.g., in liquid form within a solvent such as an aqueousor non-aqueous liquid, or within a solid carrier); intravenously (e.g.,within a dextrose or saline solution); as an infusion or injection(e.g., as a suspension or as an emulsion in a pharmaceuticallyacceptable liquid or mixture of liquids); intrathecally;intracerebroventricularly; or transdermally (e.g., using a transdermalpatch). Although it is possible to administer the compounds in the formof a bulk active chemical, it is preferred to present each compound inthe form of a pharmaceutical composition or formulation for efficientand effective administration. Exemplary methods for administering suchcompounds will be apparent to the skilled artisan. For example, thecompounds can be administered in the form of a tablet, a hard gelatincapsule or as a time-release capsule. As another example, the compoundscan be delivered transdermally using the types of patch technologiesavailable from Novartis and Alza Corporation. The administration of thepharmaceutical compositions of the present invention can beintermittent, or at a gradual, continuous, constant or controlled rateto a warm-blooded animal, (e.g., a mammal such as a mouse, rat, cat,rabbit, dog, pig, cow, or monkey); but advantageously is preferablyadministered to a human being. In addition, the time of day and thenumber of times per day that the pharmaceutical formulation isadministered can vary. Administration preferably is such that the activeingredients of the pharmaceutical formulation interact with receptorsites within the body of the subject that affect the functioning of theCNS or of the gastrointestinal (GI) tract. More specifically, intreating a CNS disorder administration preferably is such so as tooptimize the effect upon those relevant receptor subtypes which have aneffect upon the functioning of the CNS, while minimizing the effectsupon muscle-type receptor subtypes. Other suitable methods foradministering the compounds of the present invention are described inU.S. Pat. No. 5,604,231 to Smith et al., the disclosure of which isincorporated herein by reference in its entirety.

The appropriate dose of the compound is that amount effective to preventoccurrence of the symptoms of the disorder or to treat some symptoms ofthe disorder from which the patient suffers. By “effective amount”,“therapeutic amount” or “effective dose” is meant that amount sufficientto elicit the desired pharmacological or therapeutic effects, thusresulting in effective prevention or treatment of the disorder. Thus,when treating a CNS disorder, an effective amount of compound is anamount sufficient to pass across the blood-brain barrier of the subject,to bind to relevant receptor sites in the brain of the subject, and toactivate relevant nicotinic receptor subtypes (e.g., provideneurotransmitter secretion, thus resulting in effective prevention ortreatment of the disorder). Prevention of the disorder is manifested bydelaying the onset of the symptoms of the disorder. Treatment of thedisorder is manifested by a decrease in the symptoms associated with thedisorder or an amelioration of the recurrence of the symptoms of thedisorder.

The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,and the manner in which the pharmaceutical composition is administered.For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount sufficient to activaterelevant receptors to effect neurotransmitter (e.g., dopamine) releasebut the amount should be insufficient to induce effects on skeletalmuscles and ganglia to any significant degree. The effective dose ofcompounds will of course differ from patient to patient but in generalincludes amounts starting where CNS effects or other desired therapeuticeffects occur, but below the amount where muscular effects are observed.

The doses depend on the desired effect, the duration of treatment andthe administration route used; they are generally between 0.05 mg and100 mg of active substance per day orally for an adult.

Generally speaking, the doctor will determine the appropriate dosage asa function of the age, weight and all the other factors specific to thepatient.

The compounds preferably have the ability to pass across the blood-brainbarrier of the patient. As such, such compounds have the ability toenter the central nervous system of the patient. The log P values oftypical compounds, which are useful in carrying out the presentinvention are generally greater than about 0, often are greater thanabout 0.5, and frequently are greater than about 1. The log P values ofsuch typical compounds generally are less than about 3.5, often are lessthan about 3, and sometimes are less than about 2.5. Log P valuesprovide a measure of the ability of a compound to pass across adiffusion barrier, such as a biological membrane. See, Hansch, et al.,J. Med. Chem. 11:1 (1968).

The compounds have the ability to bind to, and in most circumstances,cause activation of, nAChRs of the brain of the patient (e.g., such asthose receptors that modulate dopamine release). As such, such compoundshave the ability to express nicotinic pharmacology, and in particular,to act as nicotinic agonists or partial agonists. The receptor bindingconstants of typical compounds useful in carrying out the presentinvention generally exceed about 0.1 nM, often exceed about 1 nM, andfrequently exceed about 10 nM. The receptor binding constants of suchtypical compounds generally are less than about 1 μM, often are lessthan about 100 nM, and frequently are less than about 50 nM. Receptorbinding constants provide a measure of the ability of the compound tobind to half of the relevant receptor sites of certain brain cells ofthe patient. See, Cheng, et al., Biochem. Pharmacol. 22:3099 (1973).

The compounds useful according to the method of the present inventionhave the ability to demonstrate a nicotinic function by effectivelyeliciting ion flux through, and/or neurotransmitter secretion from,nerve ending preparations (e.g., thalamic or striatal synaptosomes). Assuch, such compounds have the ability to cause relevant neurons tobecome activated, and to release or secrete acetylcholine, dopamine, orother neurotransmitters. Generally, typical compounds useful in carryingout the present invention effectively provide for relevant receptoractivation in amounts of at least about 30 percent, often at least about50 percent, and frequently at least about 75 percent, of that maximallyprovided by (S)-(−)-nicotine. Generally, typical compounds useful incarrying out the present invention are more potent than (S)-(−)-nicotinein eliciting relevant receptor activation. Generally, typical compoundsuseful in carrying out the present invention effectively provide for thesecretion of dopamine in amounts of at least about 50 percent, often atleast about 75 percent, and frequently at least about 100 percent, ofthat maximally provided by (S)-(−)-nicotine. Certain compounds of thepresent invention can provide secretion of dopamine in an amount whichcan exceed that maximally provided by (S)-(−)-nicotine. Generally,typical compounds useful in carrying out the present invention are lesspotent than (S)-(−)-nicotine in eliciting neurotransmitter secretion,such as dopamine secretion.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, lack theability to elicit activation of nAChRs of human muscle to anysignificant degree. In that regard, the compounds of the presentinvention demonstrate poor ability to cause isotopic rubidium ion fluxthrough nAChRs in cell preparations expressing muscle-type nicotinicacetylcholine receptors. Thus, such compounds exhibit receptoractivation constants or EC50 values (i.e., which provide a measure ofthe concentration of compound needed to activate half of the relevantreceptor sites of the skeletal muscle of a patient) which are extremelyhigh (i.e., greater than about 100 μM). Generally, typical preferredcompounds useful in carrying the present invention activate isotopicrubidium ion flux by less than 10 percent, often by less than 5 percent,of that maximally provided by S(−) nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, lack theability to elicit activation of human ganglion nAChRs to any significantdegree. This selectivity of the compounds of the present inventionagainst those nAChRs responsible for cardiovascular side effects isdemonstrated by a lack of the ability of those compounds to activatenicotinic function of adrenal chromaffin tissue. As such, such compoundshave poor ability to cause isotopic rubidium ion flux through nAChRs incell preparations derived from the adrenal gland. Generally, typicalpreferred compounds useful in carrying out the present inventionmaximally activate isotopic rubidium ion flux by less than 10 percent,often by less than 5 percent, of that maximally provided by S(−)nicotine.

The compounds are effective towards providing some degree of preventionof the progression of CNS disorders, ameliorating the symptoms of CNSdisorders, and ameliorating to some degree the recurrence of CNSdisorders. However, such effective amounts of those compounds are notsufficient to elicit any appreciable undesired nicotinic effects, as isdemonstrated by decreased effects on preparations believed to reflecteffects on the cardiovascular system, or effects to skeletal muscle. Assuch, administration of compounds of the present invention provides atherapeutic window in which treatment of certain CNS disorders isprovided, and undesired peripheral nicotinic effects/side effects areavoided. That is, an effective dose of a compound of the presentinvention is sufficient to provide the desired effects upon the CNS, butis insufficient (i.e., is not at a high enough level) to provideundesirable side effects. Preferably, effective administration of acompound of the present invention resulting in treatment of CNSdisorders occurs upon administration of less than ⅓, frequently lessthan ⅕, and often less than 1/10, that amount sufficient to cause anyside effects to a significant degree.

SYNTHETIC EXAMPLES

The following synthetic examples are provided to illustrate the presentinvention, and should not be construed as limiting thereof. In theseexamples, all parts and percentages are by weight, unless otherwisenoted. Reaction yields are reported in mole percentages.

Example 1 Racemic3-((E)-2-Pyrrolidin-3-ylvinyl)-5-(tetrahydropyran-4-yloxy)pyridinehemigalactarate

Trifluoroacetic acid (0.91 cm³, 11.7 mmol) was added drop-wise to asolution of 0.44 g (1.17 mmol) of racemic3-{(E)-2-[5-(tetrahydropyran-4-yloxy)pyridin-3-yl]vinyl}pyrrolidine-1-carboxylicacid tert-butyl ester in 4.5 cm³ of dichloromethane, which was underargon and was cooled to 0° C. The reaction mixture was stirred at thistemperature for 0.5 h and then at a temperature in the region of 22° C.for 20 h and was concentrated to dryness under reduced pressure (2.7kPa). The oily residue was taken up in 5 cm³ of water and the resultingsolution was rendered basic (pH=8) by adding 28% aqueous ammoniasolution and then extracted with 3 times 25 cm³ of dichloromethane. Thecombined organic phases were washed with 25 cm³ of water, dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (2.7 kPa) to give 0.225 g of orange-colored oil, which waspurified by chromatography on silica gel [eluent:dichloromethane/methanol (9/1 then 8/2 by volume)]. Concentration of thefractions under reduced pressure (2.7 kPa) gave 0.1 g (0.36 mmol) oforange-colored oil. Galactaric acid (0.038 g, 0.18 mmol) was added to asolution of this oil in 2 cm³ of methanol to which 0.5 cm³ of water hasbeen added. The mixture was brought to reflux and cooled to atemperature in the region of 22° C. and the insoluble material wasremoved by filtration. The filtrate was concentrated to dryness underreduced pressure (2.7 kPa) and the oily residue was taken up in 2 cm³ ofethanol. The precipitated solid was filtered off, washed with 2 cm³ ofisopropyl acetate and 2 cm³ of diisopropyl ether and then dried at 40°C. under vacuum (2.7 kPa) to give 0.088 g of racemic3-((E)-2-pyrrolidin-3-ylvinyl)-5-(tetrahydropyran-4-yloxy)pyridinehemigalactarate in the form of a beige solid. Mass spectrum (EI): m/z274 (M+), m/z 232. 1H NMR spectrum (300 MHz, (CD₃)₂SO d6 with a fewdrops of CD₃COOD d4, δ in ppm): 1.61 (m: 2H); 1.82 (m: 1H); 1.98 (m:2H); 2.17 (m: 1H); 2.96 (dd, J=10.5 and 8.5 Hz: 1H); 3.07 (m: 1H); from3.10 to 3.40 (m: 2H); 3.41 (dd, J=10.5 and 7.5 Hz: 1H); 3.50 (ddd, J=12-9.5 and 3 Hz: 2H); 3.79 (s: 1H); 3.87 (dt, J=12 and 4.5 Hz: 2H); 4.24(s: 1H); 4.69 (m: 1H); 6.43 (dd, J=16 and 7 Hz: 1H); 6.56 (d, J=16 Hz:1H); 7.49 (m: 1H); 8.20 (m: 2H).

Racemic3-{(E)-2-[5-(tetrahydropyran-4-yloxy)pyridin-3-yl]vinyl}pyrrolidine-1-carboxylicacid tert-butyl Ester can be Prepared as Follows

Palladium acetate (0.117 g, 0.52 mmol), 0.678 g (16 mmol) of lithiumchloride and 7.25 cm³ (42 mmol) of ethyldiisopropylamine were added insuccession to a solution under argon of 1.33 g (5.17 mmol) of3-bromo-5-(tetrahydropyran-4-yloxy)pyridine and 1.2 g (5.17 mmol) ofracemic 3-vinylpyrrolidine-1-carboxylic acid tert-butyl ester in 15 cm³of dimethylformamide. After 3 hours of heating at 110° C. with stirring,the reaction mixture was stirred for 2 hours at a temperature in theregion of 22° C. and then concentrated to dryness under reduced pressure(2.7 kPa). The oily residue was taken up in 50 cm³ of ethyl acetate andthe resulting solution was washed in succession with 2 times 25 cm³ ofwater, 25 cm³ of saturated bicarbonate solution, 2 times 25 cm³ of waterand 25 cm³ of saturated sodium chlorine solution and then was dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (2.7 kPa) to give 1.4 g of brown oil. This residue was purifiedby chromatography on silica gel [eluent: cyclohexane/ethyl acetate (8/2by volume)]. Concentration of the fractions under reduced pressure (2.7kPa) gave 0.44 g of yellow oil which was used without furtherpurification in the remainder of the synthesis.

3-Bromo-5-(tetrahydropyran-4-yloxy)pyridine can be Prepared as Follows

Diethyl azodicarboxylate (7.1 cm³, 45 mmol) was added drop-wise to asolution under argon of 5.22 g (30 mmol) of 5-bromopyridin-3-ol, 4.69 g(45 mmol) of tetrahydropyran-4-ol (45 mmol) and 11.8 g (45 mmol) oftriphenylphosphine in 150 cm³ of toluene. After 20 hours of heatingunder reflux with stirring, the reaction mixture was brought to atemperature in the region of 22° C. and then washed in succession with 2times 75 cm³ of water, 2 times 75 cm³ of saturated bicarbonate solution,2 times 75 cm³ of water and 75 cm³ of saturated sodium chloride solutionand then the organic solution was dried over magnesium sulfate, filteredand concentrated to dryness under reduced pressure (2.7 kPa) to give anorange-colored oil. This residue was admixed with 100 cm³ of diisopropylether and the solid formed was filtered off and washed with 2 times 25cm³ of diisopropyl ether. The filtrate was concentrated to dryness underreduced pressure (2.7 kPa) to give 10 g of an orange-colored oil. Thisresidue was purified by chromatography on silica gel [eluent:cyclohexane/ethyl acetate (8/2 by volume)]. Concentration of thefractions under reduced pressure (2.7 kPa) gave 7.3 g of3-bromo-5-(tetrahydropyran-4-yloxy)pyridine in the form of a yellow oil.1H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.59 (m: 2H); 1.99 (m:2H); 3.49 (ddd, J=12.5-9.5 and 3 Hz: 2H); 3.87 (dt, J=12.5 and 4.5 Hz:2H); 4.75 (m: 1H); 7.82 (dd, J=2.5 and 2 Hz: 1H); 8.28 (d, J=2 Hz: 1H);8.33 (d, J=2.5 Hz: 1H).

Racemic 3-vinylpyrrolidine-1-carboxylic acid tert-butyl Ester can bePrepared as Follows

n-Butyllithium in hexane (44 cm³ of a 1.6 N solution) was addeddrop-wise to a suspension of 25.5 g (71 mmol) oftriphenylmethylphosphonium bromide in 300 cm³ of tetrahydrofuran, whichwas under argon and cooled to 0° C. The reaction mixture was stirred at0° C. for 0.5 h and then admixed with a solution of 7.1 g (35.6 mmol) ofracemic 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester in 100cm³ of tetrahydrofuran. After 2.5 hours of reaction at a temperature inthe region of 22° C., the mixture was poured into 600 cm³ of saturatedaqueous ammonium chloride solution. Following addition of ethyl acetatethe organic phase was taken off by decanting, washed twice with waterand with saturated sodium chloride solution and then dried overmagnesium sulfate and concentrated to dryness under reduced pressure(2.7 kPa). The resulting oil was purified by chromatography on silicagel [eluent: cyclohexane/ethyl acetate (95/5 then 9/1 by volume)].Concentration of the fractions under reduced pressure (2.7 kPa) gave 6.3g of racemic 3-vinylpyrrolidine-1-carboxylic acid tert-butyl ester inthe form of a colorless oil. Mass spectrum (ES): m/z 198 (MH+), m/z=142.

Example 2 Racemic 5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidinehemigalactarate

Trifluoroacetic acid (1.2 cm³, 15.6 mmol) was added drop-wise to asolution of 0.43 g (1.56 mmol) of racemic3-((E)-2-pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acid tert-butylester in 6 cm3 of dichloromethane, which was under argon and cooled to0° C. The reaction mixture was stirred at this temperature for 0.5 hthen at a temperature in the region of 22° C. for 20 hours and it wasconcentrated to dryness under reduced pressure (2.7 kPa). The oilyresidue was taken up in 5 cm³ of water and the resulting solution wasrendered basic (pH=8) by adding 28% aqueous ammonia solution and wasthen extracted with 3 times 25 cm³ of dichloromethane. The combinedorganic phases were washed with 25 cm³ of water, dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kPa) to give 0.126 g of orange-colored oil which was purified bychromatography on silica gel [eluent: dichloromethane/methanol (9/1 then8/2 by volume)]. Concentration of the fractions under reduced pressure(2.7 kPa) gave 0.1 g (0.57 mmol) of orange-colored oil. Galactaric acid(0.06 g, 0.28 mmol) was added to a solution of this oil in 2 cm³ ofmethanol to which 0.5 cm³ of water has been added. The mixture wasbrought to reflux and cooled to a temperature in the region of 22° C.and the insoluble material was removed by filtration. The filtrate wasconcentrated to dryness under reduced pressure (2.7 kPa) and the oilyresidue was taken up in 2 cm³ of ethanol. The precipitated solid wasfiltered off, washed with 2 cm³ of isopropyl acetate and 2 cm³ ofdiisopropyl ether and then dried at 40° C. under vacuum (2.7 kPa) togive 0.1 g of racemic 5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidinehemigalactarate in the form of an ochre solid. Mass spectrum (DCI): m/z176 (MH+). 1H NMR spectrum (300 MHz, (CD₃)₂SO d6 with a few drops ofCD₃COOD d4, δ in ppm): 1.82 (m: 1H); 2.18 (m: 1H); 2.98 (dd, J=11 and8.5 Hz: 1H); 3.10 (m: 1H); 3.20 (m: 1H); 3.33 (m: 1H); 3.42 (dd, J=11and 7.5 Hz: 1H); 3.79 (s:1H); 4.24 (s: 1H); 6.55 (limit AB: 2H); 8.87(s: 2H); 9.04 (s: 1H).

Racemic 3-((E)-2-pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acidtert-butyl Ester can be Prepared as Follows

Palladium acetate (0.117 g, 0.52 mmol), 0.678 g (16 mmol) of lithiumchloride and 7.25 cm³ (42 mmol) of ethyldiisopropylamine were added insuccession to a solution under argon of 0.822 g (5.17 mmol) of5-bromopyrimidine and 1.2 g (5.17 mmol) of racemic3-vinylpyrrolidine-1-carboxylic acid tert-butyl ester in 15 cm³ ofdimethylformamide. After 3 hours of heating at 110° C. with stirring,the reaction mixture was stirred for 2 hours at a temperature in theregion of 22° C. and then concentrated to dryness under reduced pressure(2.7 kPa). The oily residue was taken up in 50 cm³ of ethyl acetate andthe resulting solution was washed in succession with 2 times 25 cm³ ofwater, 25 cm³ of saturated bicarbonate solution, 2 times 25 cm³ of waterand 25 cm³ of saturated sodium chloride solution and was then dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (2.7 kPa) to give 1.1 g of brown oil. This residue was purifiedby chromatography on silica gel [eluent: cyclohexane/ethyl acetate (8/2by volume)]. Concentration of the fractions under reduced pressure (2.7kPa) gave 0.43 g of racemic3-((E)-2-pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acid tert-butylester in the form of an oil. 1H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ inppm): 1.42 (s: 9H); 1.78 (m: 1H); 2.05 (m: 1H); from 2.90 to 3.15 (m:2H); from 3.15 to 3.60 (m: 3H); 6.51 (d, J=16.5 Hz: 1H); 6.64 (dd,J=16.5 and 7 Hz: 1H); 8.89 (s: 2H); 9.04 (s: 1H).

Example 3 (+)-5-((E)-2-Pyrrolidin-3-ylvinyl)pyrimidine galactarate

Trimethylsilyl iodide (0.2 cm³, 1.4 mmol) was added at a temperature inthe region of 22° C. to a solution under argon of 0.26 g (0.944 mmol) of(+)-3-((E)-2-pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acidtert-butyl ester in 10 cm³ of dichloromethane. After 2 hours of stirringat this temperature the reaction mixture was admixed with 15 cm³ of 5%aqueous ammonia solution and stirred for 1 hour at a temperature in theregion of 22° C. and left to settle. The aqueous phase was separated andextracted with dichloromethane. The combined organic phases were washedtwice with water and with saturated aqueous sodium chloride solution andwere then dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure (2.7 kPa) to give 0.06 g oforange-colored oil. Galactaric acid (0.035 g, 0.16 mmol) was added to asolution of this oil in 6 cm³ of methanol to which 0.6 cm³ of water hasbeen added. The mixture was brought to reflux, cooled to a temperaturein the region of 22° C. and concentrated to dryness under reducedpressure (2.7 kPa). The oily residue was triturated in the presence of 5cm³ of diisopropyl ether and the solid formed was filtered off and thendried at 45° C. under vacuum (2.7 kPa) to give 0.072 g of(+)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine galactarate in the form ofa yellow solid. Mass spectrum (DCI): m/z=176 (MH+). ¹H NMR spectrum (300MHz, (CD₃)₂SO d6 with a few drops of CD₃COOD d4, δ in ppm): 1.81 (m:1H); 2.19 (m: 1H); 2.98 (dd, J=11 and 9 Hz: 1H); 3.10 (m: 1H); 3.21 (m:1H); 3.33 (m: 1H); 3.43 (dd, J=11 and 8 Hz: 1H); 3.79 (s: 2H); 4.25 (s:2H); 6.56 (limit AB: 2H); 8.88 (s: 2H); 9.05 (s: 1H).

(+)-3-((E)-2-Pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acidtert-butyl Ester can be Prepared as Follows

A racemic mixture of3-((E)-2-pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acid tert-butylester (0.5 g) was injected in two parts on a 8 cm diameter columncontaining 1.2 kg of chiral stationary phase Chiralpak AS TM 20 μm[flow: 130 ml/min, eluent: heptane/methanol/ethanol (98/1/1 by volume)].Concentration of the fractions under reduced pressure (2.7 kPa) gave0.24 g of (+)-((E)-2 -Pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acidtert-butyl ester and 0.27 g of(−)-((E)-2-Pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acid tert-butylester. (+)-((E)-2-Pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acidtert-butyl ester was eluted in first position with a retention time of14.2 min on a 4.6 mm diameter and 250 mm length Chiralpak AS TM 20 μmcolumn [flow: 1 ml/min, eluent: heptane/methanol/ethanol (98/1/1 byvolume)]. ¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.43 (s:9H); 1.79 (m: 1H); 2.06 (m: 1H); from 2.95 to 3.15 (m: 2H); from 3.20 to3.35 (m: 1H); 3.44 (ddd, J=11-8.5 and 3 Hz: 1H); 3.53 (broad dd, J=10and 7.5 Hz: 1H); 6.52 (d, J=16.5 Hz: 1H); 6.63 (dd, J=16.5 and 7 Hz:1H); 8.89 (s: 2H); 9.04 (s: 1H).

(−)-((E)-2-Pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acid tert-butylester was eluted in second position with a retention time of 17 min on a4.6 mm diameter and 250 mm length Chiralpak AS TM 20 μm column [flow: 1ml/min, eluent: heptane/methanol/ethanol (98/1/1 by volume)]. ¹H NMRspectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.43 (s: 9H); 1.79 (m: 1H);2.06 (m: 1H); from 2.95 to 3.15 (m: 2H); from 3.20 to 3.35 (m: 1H); 3.44(ddd, J=11-8.5 and 3 Hz: 1H); 3.53 (broad dd, J=10 and 7.5 Hz: 1H); 6.52(d, J=16.5 Hz: 1H); 6.63 (dd, J=16.5 and 7 Hz: 1H); 8.89 (s: 2H); 9.04(s: 1H).

Example 4 (−)-5-((E)-2-Pyrrolidin-3-ylvinyl)pyrimidine galactarate

Trimethylsilyl iodide (0.2 cm³, 1.4 mmol) was added at a temperature inthe region of 22° C. to a solution under argon of 0.29 g (1.053 mmol) of(−)-3-((E)-2-pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acidtert-butyl ester in 10 cm³ of dichloromethane. After 2 hours of stirringat this temperature the reaction mixture was admixed with 15 cm³ of 5%aqueous ammonia solution, stirred for 1 h at a temperature in the regionof 22° C. and left to settle. The aqueous phase was separated off andextracted with dichloromethane. The combined organic phases were washedtwice with water and with saturated aqueous sodium chloride solution andthen were dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure (2.7 kPa) to give 0.1 g of orange-coloredoil. Galactaric acid (0.06 g, 0.28 mmol) was added to a solution of thisoil in 10 cm3 of methanol to which 1 cm³ of water has been added. Themixture was brought to reflux, cooled to a temperature in the region of22° C. and concentrated to dryness under reduced pressure (2.7 kPa). Theoily residue was triturated in the presence of 5 cm³ of diisopropylether and the solid formed was filtered and then dried at 45° C. undervacuum (2.7 kPa) to give 0.094 g of(−)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine galactarate in the form ofa yellow solid. Mass spectrum (DCI): m/z=176 (MH+). ¹H NMR spectrum (300MHz, (CD₃)₂SO d6 with a few drops of CD₃COOD d4, δ in ppm): 1.82 (m:1H); 2.19 (m: 1H); 2.98 (dd, J=11 and 9 Hz: 1H); 3.10 (m: 1H); 3.21 (m:1H); 3.32 (m: 1H); 3.43 (dd, J=11 and 7.5 Hz: 1H); 3.79 (s: 2H); 4.24(s: 2H); 6.57 (limit AB: 2H); 8.88 (s: 2H); 9.05 (s: 1H).

(−)-3-((E)-2-Pyrimidin-5-ylvinyl)pyrrolidine-1-carboxylic acidtert-butyl ester can be prepared as described in Example 3.

Example 5 Determination of Log P Value

Log P values, which have been used to assess the relative abilities ofcompounds to pass across the blood-brain barrier (Hansch, et al., J.Med. Chem. ii:1 (1968)), were calculated using the Cerius² softwarepackage Version 3.5 by Molecular Simulations, Inc.

Example 6 Evaluation of the Various Properties of RepresentativeCompounds

The following assays were be used to determine the binding affinity andother pharmacological properties of certain of the compounds describedherein, and can be used, generally, to evaluate other compounds asdescribed herein.

Radioligand Binding at Central Nervous System n-Acetylcholine Receptors(CNS nAChR)

α4β2 Subtype

Rats (female, Sprague-Dawley), weighing 150-250 g, were maintained on a12 h light/dark cycle and were allowed free access to water and foodsupplied by PMI Nutrition International, Inc. Animals were anesthetizedwith 70% CO₂, then decapitated. Brains were removed and placed on anice-cold platform. The cerebral cortex was removed and placed in 20volumes (weight:volume) of ice-cold preparative buffer (NaCl, 137 mM;KCl, 10.7 mM; KH2PO4, 5.8 mM; Na₂HPO₄, 8 mM; HEPES (free acid), 20 mM;iodoacetamide, 5 mM; EDTA, 1.6 mM; pH 7.4); PMSF, dissolved in methanolto a final concentration of 100 μM, was added, and the suspension washomogenized by Polytron. The homogenate was centrifuged at 18,000×g for20 min at 4° C. and the resulting pellet was re-suspended in 20 volumesof ice-cold water. After 60 min. incubation on ice, a new pellet wascollected by centrifugation at 18,000×g for 20 min at 4° C. The finalpellet was re-suspended in 10 volumes of buffer and stored at −20° C. Onthe day of the assay, tissue was thawed, centrifuged at 18,000×g for 20min, then re-suspended in ice-cold PBS (Dulbecco's Phosphate BufferedSaline, NaCl, 138 mM; KCl, 2.67 mM; KH₂PO₄, 1.47 mM; Na₂HPO₄, 8.1 mM;CaCl₂, 0.9 mM; MgCl₂, 0.5 mM; Invitrogen/Gibco; pH 7.4) to a finalconcentration of approximately 4 mg protein/mL. Protein was determinedby the method of Lowry et al., J. Biol. Chem. 193: 265-275 (1951), usingbovine serum albumin as the standard.

The binding of [³H]nicotine was measured using a modification of themethods of Romano et al., Science 210: 647-650 (1980) and Marks et al.,Mol. Pharmacol. 30: 427-436 (1986). The [³H]nicotine (SpecificActivity=81.5 Ci/mmol) was obtained from NEN Research Products. Thebinding of [³H]nicotine was measured using a 3 hr. incubation at 4° C.Incubations were conducted in 48-well micro-titre plates and containedabout 400 μg of protein per well in a final incubation volume of 300 μL.The incubation buffer was PBS and the final concentration of[³H]nicotine was 5 nM. The binding reaction was terminated by filtrationof the protein containing bound ligand onto glass fiber filters (GF/B,Brandel) using a Brandel Tissue Harvester at 4° C. Filters were soakedin de-ionized water containing 0.33% polyethyleneimine to reducenon-specific binding. Each filter was washed 3 times with 1 mL ofice-cold buffer. Non-specific binding was determined by inclusion of 10μM non-radioactive L-nicotine (Acros Organics) in selected wells.

The inhibition of [³H]nicotine binding by test compounds was determinedby including seven different concentrations of the test compound inselected wells. Each concentration was replicated in triplicate. IC₅₀values were estimated as the concentration of compound that inhibited 50percent of specific [³H]nicotine binding. Inhibition constants (Kivalues), reported in nM, were calculated from the IC₅₀ values using themethod of Cheng et al., Biochem. Pharmacol. 22: 3099-3108 (1973).

α7 Subtype

Rats (female, Sprague-Dawley), weighing 150-250 g, were maintained on a12 h light/dark cycle and were allowed free access to water and foodsupplied by PMI Nutrition International, Inc. Animals were anesthetizedwith 70% CO₂, then decapitated. Brains were removed and placed on anice-cold platform. The hippocampus was removed and placed in 10 volumes(weight:volume) of ice-cold preparative buffer (NaCl, 137 mM; KCl, 10.7mM; KH₂PO₄, 5.8 mM; Na₂HPO₄, 8 mM; HEPES (free acid), 20 mM;iodoacetamide, 5 mM; EDTA, 1.6 mM; pH 7.4); PMSF, dissolved in methanolto a final concentration of 100 μM, was added, and the tissue suspensionwas homogenized by Polytron. The homogenate was centrifuged at 18,000×gfor 20 min at 4° C. and the resulting pellet was re-suspended in 10volumes of ice-cold water. After 60 min incubation on ice, a new pelletwas collected by centrifugation at 18,000×g for 20 min at 4° C. Thefinal pellet was re-suspended in 10 volumes of buffer and stored at −20°C. On the day of the assay, tissue was thawed, centrifuged at 18,000×gfor 20 min, then re-suspended in ice-cold PBS (Dulbecco's PhosphateBuffered Saline, NaCl, 138 mM; KCl, 2.67 mM; KH₂PO₄, 1.47 mM; Na₂HPO₄,8.1 mM; CaCl₂, 0.9 mM; MgCl₂, 0.5 mM; lnvitrogen/Gibco; pH 7.4) to afinal concentration of approximately 2 mg protein/mL. Protein wasdetermined by the method of Lowry et al., J. Biol. Chem. 193: 265-275(1951), using bovine serum albumin as the standard.

The binding of [³H]MLA was measured using a modification of the methodsof Davies et al., Neuropharmacol. 38: 679-690, 1999). [³H]MLA (SpecificActivity=25-35 Ci/mmol) was obtained from Tocris. The binding of [³H]MLAwas determine using a 2 h incubation at 21° C. Incubations wereconducted in 48-well micro-titre plates and contained 300 g of proteinper well in a final incubation volume of about 200 μL. The incubationbuffer was PBS and the final concentration of [³H]MLA was 5 nM. Thebinding reaction was terminated by filtration of the protein containingbound ligand onto glass fiber filters (GF/B, Brandel) using a BrandelTissue Harvester at room temperature. Filters were soaked in de-ionizedwater containing 0.33% polyethyleneimine to reduce non-specific binding.Each filter was washed 3 times with 1 mL of PBS at room temperature.Non-specific binding was determined by inclusion of 50 μM nonradioactiveMLA in selected wells.

The inhibition of [³H]MLA binding by test compounds was determined byincluding seven different concentrations of the test compound inselected wells. Each concentration was replicated in triplicate. IC₅₀values were estimated as the concentration of compound that inhibited 50percent of specific [³H]MLA binding. Inhibition constants (Ki values),reported in nM, were calculated from the IC₅₀ values using the method ofCheng et al., Biochem. Pharmacol. 22: 3099-3108 (1973).

Determination of Dopamine Release

Dopamine release was measured using striatal synaptosomes obtained fromrat brain, according to the procedures set forth by Rapier et al., J.Neurochem. 54: 937-45 (1990). Rats (female, Sprague-Dawley), weighing150-250 g, were maintained on a 12 h light/dark cycle and were allowedfree access to water and food supplied by PMI Nutrition International,Inc. Animals were anesthetized with 70% CO₂, then decapitated. Thebrains were quickly removed and the striata dissected. Striatal tissuefrom 2 rats was pooled and homogenized in 5 ml of ice-cold 0.32 Msucrose containing 5 mM HEPES, pH 7.4, using a glass/glass homogenizer.The tissue was then centrifuged at 1,000×g for 10 minutes. The pelletwas discarded and the supernatant was centrifuged at 12,000 g for 20minutes. The resulting pellet was resuspended in perfusion buffercontaining monoamine oxidase inhibitors (128 mM NaCl, 1.2 mM KH₂PO₄, 2.4mM KCl, 3.2 mM CaCl₂, 1.2 mM MgSO₄, 25 mM HEPES, 1 mM ascorbic acid,0.02 mM pargyline HCl and 10 mM glucose, pH 7.4) and centrifuged for 15minutes at 25,000 g. The final pellet was resuspended in 1.4 mlperfusion buffer for immediate use.

The synaptosomal suspension was incubated for 10 minutes at 37° C. torestore metabolic activity. [³H]Dopamine ([³H]DA, specific activity=28.0Ci/mmol, NEN Research Products) was added at a final concentration of0.1 μM and the suspension was incubated at 37° C. for another 10minutes. 50 μL aliquots of tissue+100 μL perfusion buffer were loadedinto the suprafusion chambers of a Brandel Suprafusion System (series2500, Gaithersburg, Md.). Perfusion buffer (room temperature) was pumpedinto the chambers at a rate of 3 ml/min for a wash period of 8 minutes.Test compound (10 μM) or nicotine (10 μM) was then applied in theperfusion stream for 40 seconds. Fractions (12 seconds each) werecontinuously collected from each chamber throughout the experiment tocapture basal release, agonist-induced peak release and to re-establishthe baseline after the agonist application. The perfusate was collecteddirectly into scintillation vials, to which scintillation fluid wasadded. [³H]DA released was quantified by scintillation counting. Foreach chamber, the integrated area of the peak was normalized to itsbaseline.

Release was expressed as a percentage of release obtained with an equalconcentration of L-nicotine. Within each assay, each test compound wasreplicated using 2-3 chambers; replicates were averaged. Whenappropriate, dose-response curves of test compound were determined. Themaximal activation for individual compounds (E_(max)) was determined asa percentage of the maximal activation induced by L-nicotine. Thecompound concentration resulting in half maximal activation (EC₅₀) ofspecific ion flux was also defined.

Selectivity vs. Peripheral nAChRs

Interaction at the Human Muscle Subtype

Activation of muscle-type nAChR was established on the human clonal lineTE671/RD, which is derived from an embryonal rhabdomyosarcoma (Strattonet al., Carcinogen 10: 899-905, 1989). These cell express receptors thathave pharmacological (Lukas et al., J. Pharmacol. Exp. Ther. 251:175-182, 1989), electrophysiological (Oswald et al., Neurosci. Lett. 96:207-212; 1989), and molecular biological profiles (Luther et al., J.Neurosci. 9: 1082-1096, 1989) similar to the muscle-type nAChR.

TE671/RD cells were maintained in proliferative growth phase accordingto routine protocols (Bencherif et al., Mol. Cell. Neurosci. 2: 52-65(1991) and Bencherif et al., J. Pharmacol. Exp. Ther. 257: 946-953(1991)). Cells were cultured in Dulbecco's modified Eagle's medium(Gibco/BRL) with 10% horse serum (Gibco BRL), 5% fetal bovine serum(HyClone, Logan Utah), 1 mM sodium pyruvate, 4 mM L-Glutamine, 50,000units penicillin-streptomycin (Irvine Scientific). When cells were 80%confluent, they were plated to 6 well polystyrene plates (Costar).Experiments were conducted when the cells reached 100% confluency.

Nicotinic acetylcholine receptor (nAChR) function was assayed using⁸⁶Rb⁺ efflux according to a method described by Lukas et al., Anal.Biochem. 175: 212-218 (1988). On the day of the experiment, growth mediawas gently removed from the well and growth media containing ⁸⁶Rubidiumchloride (10⁶ Ci/ml) was added to each well. Cells were incubated at 37°C. for a minimum of 3 hours. After the loading period, excess ⁸⁶Rb wasremoved and the cells were washed twice with label-free Dulbecco'sphosphate buffered saline (NaCl, 138 mM; KCl, 2.67 mM; KH₂PO₄, 1.47 mM;Na₂HPO₄, 8.1 mM; CaCl₂, 0.9 mM; MgCl₂, 0.5 mM; Invitrogen/Gibco, pH.7.4), taking care not to disturb the cells. Next, cells were exposed to100 μM of test compound, or 100 μM of L-nicotine (Acros Organics), orbuffer alone for 4 minutes. Following the exposure period, thesupernatant containing the released ⁸⁶Rb was removed and transferred toscintillation vials. Scintillation fluid was added and releasedradioactivity was measured by liquid scintillation counting.

Within each assay, each point had 2 replicates, which were averaged. Theamount of ⁸⁶Rb release was compared to both a positive control (100 μML-nicotine) and a negative control (buffer alone) to determine thepercent release relative to that of L-nicotine.

When appropriate, dose-response curves of test compound were determined.The maximal activation for individual compounds (E_(max)) was determinedas a percentage of the maximal activation induced by L-nicotine. Thecompound concentration resulting in half maximal activation (EC₅₀) ofspecific ion flux was also defined.

Interaction at the Rat Ganglionic Subtype

Activation of the rat ganglion nAChR were established on thepheochromocytoma clonal line PC12, which is a continuous clonal cellline of neural crest origin, derived from a tumor of the rat adrenalmedulla. These cells express ganglion-like neuronal nAChRs (see Whitinget al., Nature 327: 515-518 (1987); Lukas et al., J. Pharmacol. Exp.Ther. 251: 175-182 (1989); Whiting et al., Mol. Brain Res. 10: 61-70(1990)).

Rat PC12 cells were maintained in proliferative growth phase accordingto routine protocols (Bencherif et al., Mol. Cell. Neurosci. 2: 52-65(1991) and Bencherif et al., J. Pharmacol. Exp. Ther. 257: 946-953(1991)). Cells were cultured in Dulbecco's modified Eagle's medium(Gibco/BRL) with 10% horse serum (Gibco BRL), 5% fetal bovine serum(HyClone, Logan Utah), 1 mM sodium pyruvate, 4 mM L-Glutamine, 50,000units penicillin-streptomycin (Irvine Scientific). When cells were 80%confluent, they were plated to 6 well Nunc plates (Nunclon), coated with0.03% poly-L-lysine (Sigma, dissolved in 100 mM boric acid). Experimentswere conducted when the cells reached 80% confluency.

Nicotinic acetylcholine receptor (nAChR) function was assayed using⁸⁶Rb⁺ efflux according to a method described by Lukas et al., Anal.Biochem. 175: 212-218 (1988). On the day of the experiment, growth mediawas gently removed from the well and growth media containing ⁸⁶Rubidiumchloride (10⁶ Ci/ml) was added to each well. Cells were incubated at 37°C. for a minimum of 3 hours. After the loading period, excess ⁸⁶Rb wasremoved and the cells were washed twice with label-free Dulbecco'sphosphate buffered saline (NaCl, 138 mM; KCl, 2.67 mM; KH₂PO₄, 1.47 mM;Na₂HPO₄, 8.1 mM; CaCl₂, 0.9 mM; MgCl₂, 0.5 mM; Invitrogen/Gibco, pH.7.4), taking care not to disturb the cells. Next, cells were exposed to100 μM of test compound, or 100 μM of nicotine, or buffer alone for 4minutes. Following the exposure period, the supernatant containing thereleased ⁸⁶Rb⁺ was removed and transferred to scintillation vials.Scintillation fluid was added and released radioactivity was measured byliquid scintillation counting.

Within each assay, each point had 2 replicates, which were averaged. Theamount of ⁸⁶Rb release was compared to both a positive control (100 μMnicotine) and a negative control (buffer alone) to determine the percentrelease relative to that of L-nicotine.

When appropriate, dose-response curves of test compound were determined.The maximal activation for individual compounds (E_(max)) was determinedas a percentage of the maximal activation induced by L-nicotine. Thecompound concentration resulting in half maximal activation (EC₅₀) ofspecific ion flux was also defined.

Interaction at the Human Ganglionic Subtype

The cell line, SH-SY5Y, is a continuous line derived by sequentialsubcloning of the parental cell line, SK-N-SH, which was originallyobtained from a human peripheral neuroblastoma. SH-SY5Y cells express aganglion-like nAChR (Lukas et al., Mol. Cell. Neurosci. 4: 1-12, 1993).

Human SHSY5Y cells were maintained in proliferative growth phaseaccording to routine protocols (Bencherif et al., Mol. Cell. Neurosci.2: 52-65 (1991) and Bencherif et al., J. Pharmacol. Exp. Ther. 257:946-953 (1991)). Cells were cultured in Dulbecco's modified Eagle'smedium (Gibco/BRL) with 10% horse serum (Gibco BRL), 5% fetal bovineserum (HyClone, Logan Utah), 1 mM sodium pyruvate, 4 mM L-Glutamine,50,000 units penicillin-streptomycin (Irvine Scientific). When cellswere 80% confluent, they were plated to 6 well polystyrene plates(Costar). Experiments were conducted when the cells reached 100%confluency.

Nicotinic acetylcholine receptor (nAChR) function was assayed using⁸⁶Rb⁺ efflux according to a method described by Lukas et al., Anal.Biochem. 175: 212-218 (1988). On the day of the experiment, growth mediawas gently removed from the well and growth media containing ⁸⁶Rubidiumchloride (10⁶ Ci/ml) was added to each well. Cells were incubated at 37°C. for a minimum of 3 hours. After the loading period, excess ⁸⁶Rb⁺ wasremoved and the cells were washed twice with label-free Dulbecco'sphosphate buffered saline (NaCl, 138 mM; KCl, 2.67 mM; KH₂PO₄, 1.47 mM;Na₂HPO₄, 8.1 mM; CaCl₂, 0.9 mM; MgCl₂, 0.5 mM; Invitrogen/Gibco, pH.7.4), taking care not to disturb the cells. Next, cells were exposed to100 μM of test compound, or 100 μM of nicotine, or buffer alone for 4minutes. Following the exposure period, the supernatant containing thereleased ⁸⁶Rb was removed and transferred to scintillation vials.Scintillation fluid was added and released radioactivity was measured byliquid scintillation counting.

Within each assay, each point had 2 replicates, which were averaged. Theamount of ⁸⁶Rb release was compared to both a positive control (100 μMnicotine) and a negative control (buffer alone) to determine the percentrelease relative to that of L-nicotine.

When appropriate, dose-response curves of test compound were determined.The maximal activation for individual compounds (E_(max)) was determinedas a percentage of the maximal activation induced by L-nicotine. Thecompound concentration resulting in half maximal activation (EC₅₀) ofspecific ion flux was also defined.

Representative compounds were evaluated using the assays describedherein. The results indicate that the compounds of the present inventionselectively bind at α4β2 nAChRs and consequently elicit dopaminerelease. Typically, Ki values for binding at α4β2 are in the range 1-100nM, and E_(max) values for dopamine release approach 100% of thatproduced by nicotine. In contrast, the compounds of the presentinvention do not bind well at those subtypes of the nAChR which arecharacteristic of the peripheral nervous and muscular systems. Thus, thecompounds of the present invention possess therapeutic potential intreating central nervous system disorders without producing side effectsassociated with interaction with the peripheral nervous system.

Having disclosed the subject matter of the present invention, it shouldbe apparent that many modifications, substitutions and variations of thepresent invention are possible in light thereof. It is to be understoodthat the present invention can be practiced other than as specificallydescribed. Such modifications, substitutions and variations are intendedto be within the scope of the present application.

1. A vinylazacycloalkane compound of Formula (I):

wherein: the wavy line represents E geometry about the double bond; X isCR²; R¹ is hydrogen, C₁₋₆-alkyl, halogen, —OR⁴, —NR⁴R⁵, or —SR⁴; R² ishydrogen, C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, heteroaryl,heteroaryl-C₁₋₆-alkyl, heterocyclyl, heterocyclyl-C₁₋₆-alkyl,cycloalkyl, polycycloalkyl, —OR⁶, —NR⁶R⁷, —SR⁶, —SOR⁶, or —SO₂R⁶,wherein the C₁₋₆-alkyl, cycloalkyl, heterocyclyl, heteroaryl, or arylgroups may be substituted with one or more substituents selected fromthe group consisting of F, CI, Br, I, —R⁸, —OR⁸, —NR⁸R⁹, —CF₃, —OCF₃,—CN, —NO₂, —SR⁸, —S(O)R⁸, —SO₂R⁸, —O—SO₂R⁸, —C(═O)NR⁸R⁹, —NR⁸C(═O)R⁹,—C(═O)OR⁸, —OC(═O)R⁸, —NHSO₂R⁸, —SO₂NR⁸R⁹, —C(S)NR⁸R⁹, and —NHC(S)R⁸; R³is hydrogen or methyl; R⁴ and R⁵ are, independently, hydrogen orC₁₋₆-alkyl; R⁶ and R⁷ are, independently, hydrogen, C₁₋₆-alkyl, aryl,aryl-C₁₋₆-alkyl, heteroaryl, heteroaryl-C₁₋₆-alkyl, heterocyclyl,heterocyclylalkyl, cycloalkyl, or polycycloalkyl, wherein theC₁₋₆-alkyl, cycloalkyl, heterocyclyl, heteroaryl and aryl groups can besubstituted with one or more substituents selected from the groupconsisting of F, CI, Br, I, —R⁸, —NR⁸R⁹, —CF₃, —CN, —NO₂, —C₂R⁸, —N₃,—SO₂CH₃, —OR⁸, —SR⁸, —C(═O)NR⁸R⁹, —NR⁸C(═O)R⁸, —C(═O)R⁸, —C(═O)OR⁸,—(CH₂)_(q)OR⁸, —OC(═O)R⁸, —OC(═O)NR⁸R⁹, and —NR⁸C(═O)OR⁸; R⁸ and R⁹ are,independently, hydrogen, C₁₋₆-alkyl, or an aromatic group-containingspecies, wherein the aromatic group-containing species can besubstituted with one or more of C₁₋₆-alkyl, halogen, or amino; or eitherR⁶ and R⁷ together or R⁸ and R⁹ together with the atoms to which theyare attached form a 3- to 10-membered ring; m is 1, 2, 3, or 4; and n is1, 2, or 3; or an enantiomer, diastereomer, tautomer, orpharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein the wavy line represents variable geometry (E or Z) about thedouble bond; provided that when R¹ and R² each are hydrogen, then R³ ishydrogen; provided that when R¹ is hydrogen, R² is —OR⁶, and R⁶ isphenyl, then R³ is hydrogen; provided that when R¹ is hydrogen, R² is—OR⁶, and R⁶ is ethyl, then R³ is hydrogen; and provided that when R² is—OR⁶, R⁶ is isopropyl, and R³ is either hydrogen or methyl, then R¹ isother than hydrogen.
 3. The compound of claim 1 wherein the wavy linerepresents variable geometry (E or Z) about the double bond; X is CR²;R¹ is hydrogen, C₁₋₆-alkyl, halogen, —OR⁴, —NR⁴R⁵, or —SR⁴; R² is —OR⁶;R³ is hydrogen or methyl; R⁴ and R⁵ are, independently, hydrogen orC₁₋₆-alkyl; R⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, isopentyl,sec-pentyl, tert-pentyl, hexyl, phenyl, naphthyl, indenyl,phenyl-C₁₋₆-alkyl, naphthyl-C₁₋₆-alkyl, indenyl-C₁₋₆-alkyl, heteroaryl,heteroaryl-C₁₋₆-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, orpolycycloalkyl, wherein the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, isopentyl,sec-pentyl, tert-pentyl, hexyl, phenyl, naphthyl, indenyl, cycloalkyl,heterocyclyl, and heteroaryl groups can be substituted with one or moresubstituents selected from the group consisting of F, CI, Br, I, —R⁸,—NR⁸R⁹, —CF₃, —CN, —NO₂, —C₂R⁸, —N₃, —SO₂CH₃, —OR⁸, —SR⁸, —C(═O)NR⁸R⁹,—NR⁸C(═O)R⁸, —C(═O)R⁸, —C(═O)OR⁸, —(CH₂)_(q)OR⁸, —OC(═O)R⁸,—OC(═O)NR⁸R⁹, and —NR⁸C(═O)OR⁸; R⁸ and R⁹ are, independently, hydrogen,C₁₋₆-alkyl, or an aromatic group-containing species, wherein thearomatic group-containing species can be substituted with one or more ofC₁₋₆-alkyl, halogen, or amino; or R⁸ and R⁹ together with the atoms towhich they are attached form a 3- to 10-membered ring; m is 1,2,3, or 4;and n is 1, 2, or 3; or an isomer, mixture, enantiomer, diastereomer,tautomer, or pharmaceutically acceptable salt thereof; provided thatwhen R¹ and R² each are hydrogen, then R³ is hydrogen; provided thatwhen R¹ is hydrogen and R⁶ is phenyl, then R³ is hydrogen; provided thatwhen R¹ is hydrogen and R⁶ is ethyl, then R³ is hydrogen; provided thatwhen R⁶ is isopropyl, and R³ is either hydrogen or methyl, then R¹ isother than hydrogen.
 4. The compound of claim 3 wherein the wavy linerepresents E geometry.
 5. The compound of claim 1, wherein the aromaticgroup-containing species is pyridyl, quinolinyl, pyrimidinyl, phenyl, orbenzyl.
 6. The compound of claim 1, wherein R¹ is H.
 7. The compound ofclaim 1, wherein R² is —OR⁶.
 8. The compound of claim 1, wherein n is 1.9. The compound of claim 1, wherein m is
 2. 10. The compound of claim 1,wherein R⁶ is heterocyclyl.
 11. The compound of claim 1, wherein R¹ isH; R² is —OR⁶; n is 1; m is 2; R⁶ is heterocyclyl; and the wavy linerepresents E geometry.
 12. A compound selected from the group consistingof: (R)- and (S)-2-chloro-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine; (R)-and (S)-3-cyclopropylmethoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine;(R)- and (S)-2-chloro-5-((E)-2-piperidin-3-ylvinyly pyridine; (R)- and(S)-3-cyclopropylmethoxy-5-((E)-2-piperidin-3-ylvinyl)pyridine; and2-chloro-5-((E)-2-piperidin-4-ylvinyl)pyridine; or an enantiomer,diastereomer, tautomer, or pharmaceutically acceptable salt thereof. 13.A pharmaceutical composition comprising a compound of claim 1 and atleast one pharmaceutically acceptable carrier.
 14. The pharmaceuticalcomposition of claim 13, further comprising an additional activecomponent.
 15. A process for preparing arylvinylazacycloalkane compoundsof formula

wherein: the wavy line represents variable geometry (E or Z) about thedouble bond; X is CR²; R¹ is hydrogen, C₁₋₆-alkyl, halogen, —OR^(4, —NR)⁴R⁵, or —SR⁴; R² is hydrogen, C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,heteroaryl, heteroaryl-C₁₋₆-alkyl, heterocyclyl,heterocyclyl-C₁₋₆-alkyl, cycloalkyl, polycycloalkyl, —OR⁶, —NR⁶R⁷, —SR⁶,—SOR⁶, or —SO₂R⁶, wherein the C₁₋₆-alkyl, cycloalkyl, heterocyclyl,heteroaryl, or aryl groups may be substituted with one or moresubstituents selected from the group consisting of F, CI, Br, I, —R⁸,—OR⁸, —NR⁸R⁹, —CF₃, —OCF₃, —CN, —NO₂, —SR⁸, —S(O)R⁸, —SO₂R⁸, —O—SO₂R⁸,—C(═O)NR⁸R⁹, —NR⁸C(═O)R⁹, —C(═O)OR⁸, —OC(═O)R⁸, —NHSO₂R⁸, —SO₂NR⁸R⁹,—C(S)NR⁸R⁹, and -NHC(S)R⁸; R³ is hydrogen or methyl; R⁴ and R⁵ are,independently, hydrogen or C₁₋₆-alkyl; R⁶ and R⁷ are, independently,hydrogen, C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, heteroaryl,heteroaryl-C₁₋₆-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, orpolycycloalkyl, wherein the C₁₋₆-alkyl, cycloalkyl, heterocyclyl,heteroaryl and aryl groups can be substituted with one or moresubstituents selected from the group consisting of F, CI, Br, I, —R⁸,—NR⁸R⁹, —CF₃, —CN, —NO₂, —C₂R⁸, —N₃, —SO₂CH₃, —OR⁸, —SR⁸, —C(═O)NR⁸R⁹,—NR⁸C(═O)R⁸, —C(═O)R⁸, —C(═O)OR⁸, —(CH₂)_(q)OR⁸, —OC(═O)R⁸,—OC(═O)NR⁸R⁹, and —NR⁸C(═O)OR⁸; R⁸ and R⁹ are, independently, hydrogen,C₁₋₆-alkyl, or an aromatic group-containing species, wherein thearomatic group-containing species can be substituted with one or more ofC₁₋₆-alkyl, halogen, or amino; or either R⁶ and R⁷ together or R⁸ and R⁹together with the atoms to which they are attached form a 3- to10-membered ring; m is 1, 2, 3, or 4; and n is 1, 2, or 3; or anenantiomer, diastereomer, tautomer, or pharmaceutically acceptable saltthereof, comprising: a) reacting an aldehyde of formula

wherein m is 1, 2, or 3, and n is 1, 2, or 3; with a phosphorane ylideof the formulaPPh₃═CH₂ to yield a vinylazacycloalkane of the formula

b) reacting the resulting vinylazacycloalkane with a heteroaryl halideof the formula

wherein X and R¹ are as defined above, and Y is halogen; and c) removingany remaining protecting groups.